Peroxynitrite decomposition catalyst: hemorrhagic shock

过氧亚硝酸盐分解催化剂：失血性休克

• 批准号: 6442438
• 负责人: JON G MABLEY
• 金额: $ 27.71万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6442438
• 关键词: catalyst; drug design /synthesis /production; drug screening /evaluation; hemodynamics; hemorrhagic shock; laboratory rat; peroxynitrites; pharmacokinetics; trauma

This proposal is intended to establish a new therapeutic approach to save the lives of severely injured trauma victims with hemorrhagic shock (HS). In a small proportion of trauma, a fatal outcome is assured due to the irreversible loss of vital functions or massive blood loss. Frequently, however, emergent resuscitation is possible. These victims survive to hospitalization and are able to receive the full benefits of modern intensive care and surgery. In spite of fluid resuscitation and surgery to repair vascular and parenchymal injuries, however, not all treated patients survive HS. The principal impediment to a successful outcome in this population is the development of cardiovascular failure, a condition in which HS results in profound hypotension hypotension refractory to fluid replacement and inotropic support. There is substantial evidence that HS-induced tissue injury is mediated by profound alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion, and their reaction product peroxynitrite, a toxic oxidant. We are developing a novel metalloporphyrin that acts a speroxynitrite decomposition catalyst. Our lead compound, FP15, is dramatically protective in experimental models of ischemia-reperfusion injury. The central objective of this grant proposal is to establish that FP15 improves hemodynamics, metabolic function, end-organ injury, and survival in a rodent model of hemorrhagic shock. We will address this objective by characterizing the pharmacodynamic profile of FP15 in a rat model of severe fixed-pressure HS. We will correlate the cardiovascular (heart, rate, blood pressure), metabolic (serum lactate concentration), and survival dose-responses with serum FP15 concentrations, in order to establish a pharmacodynamic profile. The results of the present application will establish the technical merit and feasibility of FP15 as a novel parenteral therapeutic candidate for HS. PROPOSED COMMERCIAL APPLICATIONS: The annual domestic impact of hemorrhagic shock on the health care market is estimated at > $200 million. The worldwide market in hemorrhagic shock (developed countries only) is four times larger. Given the absence of a specific completely effective therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high-sustained price point ($1000 per patient). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $800 million (annual).

本建议旨在建立一种新的治疗方法，以挽救严重创伤患者失血性休克（HS）的生命。在一小部分创伤中，由于不可逆转的生命功能丧失或大量失血，造成致命的后果。然而，紧急复苏通常是可能的。这些受害者活到住院，并能够得到现代重症监护和手术的全部好处。然而，尽管进行了液体复苏和手术修复血管和实质损伤，但并非所有接受治疗的患者都能存活。在这一人群中，成功治疗的主要障碍是心血管衰竭的发展，在这种情况下，HS会导致深度低血压，对补液和肌力支持都是难治性的。有大量证据表明，hs诱导的组织损伤是由自由基一氧化氮和超氧阴离子及其反应产物过氧亚硝酸盐（一种有毒的氧化剂）的生物合成发生深刻变化介导的。我们正在开发一种新型的金属卟啉，作为亚氧化亚硝酸盐分解催化剂。我们的先导化合物FP15对缺血再灌注损伤的实验模型具有显著的保护作用。本拨款提案的中心目标是确定FP15改善出血性休克啮齿动物模型的血流动力学、代谢功能、终末器官损伤和生存率。我们将通过描述FP15在严重定压HS大鼠模型中的药效学特征来解决这一目标。我们将把心血管（心脏、心率、血压）、代谢（血清乳酸浓度）和生存剂量反应与血清FP15浓度联系起来，以建立药效学概况。本应用的结果将确定FP15作为一种新的肠外治疗候选者的技术优点和可行性。建议的商业应用：每年出血性休克对国内医疗保健市场的影响估计为10亿至2亿美元。失血性休克的全球市场（仅在发达国家）是它的四倍。鉴于目前还没有一种完全有效的治疗方法，Inotek预计市场接受度将很快提高，渗透率也会很高，价格也会保持在较高水平（每位患者1000美元）。市场进入和成熟后（FDA批准后约4年）估计全球总销售收入等于8亿美元（每年）。